Genetic Diseases SCPA202: Basic Pathology Amornrat N. Jensen, Ph.D. Department of Pathobiology School of Science, Mahidol University amornrat.nar@mahidol.ac.th Genetic disease An illness caused by abnormalities in genes or chromosomes Genetic abnormalities maybe inherited, acquired during embryogenesis, or acquired later in life 1
Genes Double-stranded molecules of DNA Four types of nucleotide base - Adenine, Thymine, Cytosine, and Guanine Cells store the hereditary information in DNA http://thapring.com DNA is packaged in a chromosome Chromosome www.dirkschweitzer.net Human Cells Chromosomes (in nucleus) Chromosome Modified from www.ncbi.nlm.nih.gov/books A gene on a chromosome 2
Human has 46 chromosomes (23 pairs) Sex chromosomes One chromosome of each pair is inherited from mother and one from father Chromosomes other than the sex chromosomes called autosomes Products of genes are specific proteins Proteins are essential molecules for living organisms 3
DNA codons are the code for each amino acid DNA Protein (protein) The genetic code for amino acids is a triplet code Image from bio.georgiasouthern.edu 4
Permanent changes in the DNA Genetic mutations Example of genetic mutation CAC CAG Histidine Normal protein Glutamine Faulty protein Example: Mutation in β o -thalassemia Kumar et al., Basic Pathology, 7th edition, 2003 5
Types of genetic disorders 1) Single gene / Mendelian disorders 2) Chromosomal disorders 3) Multifactorial / Complex disorders 4) Mitochondrial disorders 5) Epigenetic disorders Single gene / Mendelian disorders Resulted from mutations in single genes Often have simple and predictable inheritance There are over 5,000 known mendelian disorders! 6
Transmission patterns of single gene disorders 1) Autosomal dominant 2) Autosomal recessive 3) Sex chromosome-linked Dominant gene VS recessive gene Genes are always found in pairs that control the making of the same protein In some cases, one gene of the pair will control the feature - Gene that controls the feature: Dominant gene - The other gene in the pair: Recessive gene 7
Transmission pattern of autosomal dominant disorders Examples of autosomal dominant disorders Kumar et al., Basic Pathology, 7th edition, 2003 8
Huntington s disease Neurodegenerative disorder that cells in the part of the brain that controls movement, emotion, and thinking ability is destroyed Caused by a mutation in the gene encoding for huntingtin http://learn.genetics.utah.edu/ Huntingtin has been shown to be essential for development, however its function is yet unclear http://edoc.hu-berlin.de/ dissertationen/zabelclaus-2003-01-17/html/ N100BA.html Familial hypercholesterolemia The most common mendelian disorders (prevalence: 1 in 500) Caused by a mutation in gene encoded for LDL receptor LDL receptor functions in removing LDL from the blood circulation Patient with familial hypercholesterolemia has abnormally high level of LDL in the blood Kumar et al., Basic Pathology, 8th edition, 2007 9
Transmission patterns of single gene disorders 1) Autosomal dominant 2) Autosomal recessive 3) Sex chromosome-linked Autosomal recessive disorders The largest group of mendelian disorders The diseases occur only when both alleles of the genes are mutants Disease onset is usually early in life X X 10
Transmission pattern of autosomal recessive disorders Examples of autosomal recessive disorders Kumar et al., Basic Pathology, 8th edition, 2007 11
Cystic fibrosis Disease that affects the respiratory and digestive systems Mutation of gene encoding chloride channel essential for production of sweat, mucus, and digestive components Patients have salty tasting skin, poor growth, excess mucus production, frequent chest infections and shortness of breath http://learn.genetics.utah.edu Sickle cell anemia A disorder that affects red blood cells Caused by a mutation in a gene encoding for beta subunit of hemoglobin Hemoglobin molecules do not form properly, causing red blood cells to be rigid and have a concave shape http://learn.genetics.utah.edu 12
Transmission patterns of single gene disorders 1) Autosomal dominant 2) Autosomal recessive 3) Sex chromosome-linked X-linked disorders There are relatively small number of x-linked diseases Almost all x-linked disorders are recessive Female carrying one mutant x allele usually does not carry a disease due to the presence of another normal allele http://genome.wellcome.ac.uk/doc_wtd020851.html Affected male does not pass x-linked trait to his son 13
Transmission pattern of X-linked disorders http://www.web-books.com/elibrary/medicine/appendix/inheritance.htm Examples of X-linked disorders Kumar et al., Basic Pathology, 8th edition, 2007 14
Hemophilia Disorder that affects ability to control blood clotting Caused by mutations in genes encoding for clotting factors that help platelets stick together at the site of injury Patients with hemophilia have a prolonged bleeding following the injury www.ynooban.co.cc Red-green color blindness The most common form of color blindness Found in approximately 7% of male population in the US and only 0.4% of female population (Montgomery, Howard Huge Medical Institute) Caused by mutations in two genes that encode for red and green pigments 15
Types of genetic disorders 1) Single gene / Mendelian disorders 2) Chromosomal disorders 3) Multifactorial / Complex disorders 4) Mitochondrial disorders 5) Epigenetic disorders Chromosomal Disorders Approximately 1 of 200 newborns has some form of chromosomal abnormalities Chromosomal disorders/ Cytogenetic disorders are caused by: 1. Alterations in chromosome number or 2. Alterations in chromosome structure 16
Alterations in chromosome number Nondisjunction occurs when homologues fail to separate during meiosis Trisomy cell has one extra chromosome Monosomy cell has one missing chromosome Down syndrome/ Trisomy 21 Result of an extra copy of chromosome 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Affects 1 in 800 children - the most common chromosomal disorder! 19 20 21 22 23 Patients have characteristic facial features, short stature, heart defects, and short lifespan 17
Turner syndrome/ Monosomy X The only viable monosomy in humans!! Found in 1 of every 2,000 to 2,500 newborns Patients have short stature, do not mature sexually during puberty, and sterile Chromosomal abnormality 1. Alterations in chromosome number 2. Alterations in chromosome structure Translocation Deletion Duplication 18
Diseases caused by chromosomal translocations http://en.wikipedia.org Disease caused by chromosomal deletion: Cridu-Chat Syndrome Partial deletion of a small arm of chromosome 5 Severe mental retardation People who have Cri-du-chat syndrome usually cry like a cat due to abnormal larynx development, have a small head, and unusual facial features 19
Types of genetic disorders 1) Single gene / Mendelian disorders 2) Chromosomal disorders 3) Multifactorial / Complex disorders 4) Mitochondrial disorders 5) Epigenetic disorders Multifactorial or complex disorders Mutations in a number of genes, often coupled with an environmental influence (drug use, alcohol, pollutants etc.) Often cluster in families BUT do not have a clear-cut pattern of inheritance Low tendency to be inherited compared to single gene disorders 20
Example of complex multigenic disorders Asthma Diabetes Epilepsy Hypertension Coronary artery disease Types of genetic disorders 1) Single gene / Mendelian disorders 2) Chromosomal disorders 3) Multifactorial / Complex disorders 4) Mitochondrial disorders 5) Epigenetic disorders 21
Mitochondrial disorders Mitochondria contain several copies of their own genetic material (mitochondrial DNA) Only egg contribute mitochondria to the embryo while sperm does not The DNA in mitochondria is inherited only from the mother Transmission pattern of mitochondrial disorders Unaffected father Affected mother Affected father Unaffected mother Unaffected Affected Affected Children Unaffected Children 22
Examples of mitochondrial disorders Leber optic atrophy - Visual loss beginning in young adulthood Leigh's disease (Subacute Necrotizing Encephalomyelopathy) Types of genetic disorders 1) Single gene / Mendelian disorders 2) Chromosomal disorders 3) Multifactorial / Complex disorders 4) Mitochondrial disorders 5) Epigenetic disorders 23
Epigenetic disorders Caused by changes in the activity of genes, rather than a mutation in DNA Example: Cancers Cell growth Expression of genes that slow cell growth (Tumor suppressor genes) Expression of genes that increase cell growth (Proto-oncogenes) Types of genetic disorders 1) Single gene / Mendelian disorders 2) Chromosomal disorders 3) Multifactorial / Complex disorders 4) Mitochondrial disorders 5) Epigenetic disorders 24
Suggested sources for reading Basic Pathology Kumar, Abbas, Fausto, and Mitchell, 8th Edition, 2007 Genomic Disorders: The Genomic Basis of Disease. James R. Lupski, May 2006 25